Human Olfactory Ensheathing Cell-derived Extracellular Cesicles: miRNA Profile and Neuroprotective Effect

Abstract

Background: Extracellular Vesicle (EV)-based therapy has been identified as a leading alternative approach in several disease models. EV derived from the Olfactory Ensheathing Cell (OEC) has been documented for its strong neuro-regenerative capacity. However, no information on its cargo that may contribute to its therapeutic effect has been available. Objective: To report the first miRNA profile of human OEC (hOEC) -EV, and investigate the neuroprotective effects. Methods: hOEC-EV was isolated and sequenced. We established in vitro experiments to assess the therapeutic potential of hOEC-EVs with respect to insulted neural progenitor cells (NPCs), and the angiogenesis effect. Secondary post-injury insults were imitated using t-BHP-mediated oxidative stress. Results: We noted a strong abundance of hOEC-EV-miRNAs, including hsa-miR148a-3p, hasmiR151a- 3p and several members of let-7 family. The common targets of 15 miRNAs among the top 20 miRNAs were thrombospondin 1 and cyclin dependent kinase 6. We demonstrated that hOEC-EVs promote normal NPC proliferation and differentiation to neuron-like morphologies with prolonged axons. hOEC-EVs protect cells from t-BHP mediated apoptosis. We also found that the migration rate of either NPCs or endothelial cells significantly improved with hOEC-EVs. Furthermore, in vitro tube formation assays indicated that angiogenesis, an important process for tissue repair, was significantly enhanced in human umbilical vein endothelial cells exposed to hOEC-EVs. Conclusion: Our results revealed that hOEC-EVs exert neuroprotective effects by protecting cells from apoptosis and promoting in vitro biological processes that are important to neural tissue repair, including neural cell proliferation, axonal growth, and cell migration, in addition to enhancing angiogenesis.